WO2019070109A1

WO2019070109A1 - Triconjugate for treating diabetes mellitus

Info

Publication number: WO2019070109A1
Application number: PCT/MX2017/000116
Authority: WO
Inventors: Arturo Rodríguez Jacob
Original assignee: Infinite Clinical Research International, S.A. De C.V.
Priority date: 2017-10-03
Filing date: 2017-10-03
Publication date: 2019-04-11

Abstract

The invention relates to a triconjugate for treating diabetes mellitus, which consists of a pharmaceutical composition for controlling blood sugar level. The triconjugate comprises a combination of metaphormin and glibenclamide and the silibinin-phosphatidylcholine complex. The invention also relates to a method for obtaining tablets with said pharmaceutical composition.

Description

TRICONJUGADO FOR THE TREATMENT OF DIABETES MELLITUS.

BOX OF THE INVENTION The present invention is related to e! pharmaceutical sector and more specifically with the pharmaceutical sector manufacturing products for the control of blood glucose concentration.

BACKGROUND OF THE INVENTION

Diabetes Mellitus (DM) is defined as a group of metabolic diseases characterized by disorders in the metabolism of carbohydrates, lipids and proteins, which occurs due to an insufficiency in the secretion and / or action of insulin and currently this pathology constitutes a public health problem, especially 3a Diabetes Mellitus Type 2 (T2DM) (1).

Because there is no cure for Diabetes Mellitus, the drugs for the treatment of this disease are administered throughout life, which implies a considerable cost for the patient and in many cases it is not possible to access these modern treatment schemes. , this is where the fitoferapia or natural medicine arises! as an alternative treatment of equal effectiveness, but with fewer side effects characteristic of medications, in addition to being more economical. This is where the fitoferapia or natural medicine arise as an alternative treatment of effectiveness Same but with less side effects characteristic of the medicines (2). Currently working on the integration of these compounds as an alternative in the treatment, medicinal plants or their extracts can optimize the entry and / or metabolism of glucose, as well as decrease symptoms, reduce complications, improve the gyraemic control, normalize the lipid profile, antioxidant status and capillary function of diabetic patients. Si! Imarina, a mixed extract of pohyphenolic flavonoids isolated from the milk thistle (Silybum marianum), represents a new option as an alternative treatment for Diabetes Meiliius, since different beneficial properties have been identified in e! organism, for example, the positive regeneration of pancreatic tissue as well as its functionality. The extract of siiimarina constitutes approximately between 70-80% of the plant and 20-30% is made up of chemical compounds not yet identified. Siiimarin is composed of three main molecules called fiavonolignans: siiidianin, silicrisin and silybin; the latter being the most abundant (50-60%) and the most active, which is why the beneficial effect is attributed to it (3). So much so that in preclinical studies it has been demonstrated that silybin neutralizes free radicals, thus protecting the liver cells against oxidative damage. It also inhibits the adhesion of toxins, as well as the production of leukotrienes that are involved in the inflammatory response (4).

However, the low solubility in water and the low bioavailability are frequent complications with flavonoids, and this is mainly due to two factors, one of them is that they have a structure with multiple rings of large size that can not be absorbed by simple diffusion , or actively as with some vitamins or minerals. The second factor to consider is that the flavonoids have low miscibility with oils or other lipids, which affects their passage through the epididymal membrane of the enterocytes of the small intestine. To solve these complications, some methodologies have been developed, such as the creation of so-called "itosomes ", these are molecular complexes of water-miscible flavonoids linked to a lipid compound, mainly phosphatidylcholine (PC) derived from soybeans. . The hybrid bond formed by the binding of both compounds produces facilitated diffusion of the flavonoid extracts into the cell (5), in US Pat. No. 4,764,508, Gabetta-Bruno, Bombardeili-Ezio et al. Pifferi-Giorgio, the invention of phosphoiipide complexes is disclosed with three main active substances of silymarin: siSibin, siidianin and silicrisin, the latter being of alkaline origin, have a very low absorption and bioavailability rate in the gastrointestinal tract. However, this invention demonstrates that the absorption of these complexes is appreciably larger, resulting in higher plasma levels than for flavonoiignans alone. The resulting improvement in pharmacokinetics and pharmacological parameters is such that the substances can be used advantageously in the treatment of acute and chronic problems of toxic, metabolic or infectious origin, or degenerative in nature.

Additionally, there is a complex of siiibine and phosphatidylcholine 1: 2 (Siliphos®) on the market, this compound has a higher absorption, a lower therapeutic dose and a better stability profile, increasing the bioavailability and absorption of the compound (8).

Today, there are several allopathic medicines used in the market for the treatment of diabetes, among which are the groups of the suifonureas, the biguanides, the thiazolidinediones, the inhibitors of the aifa-glucosidase, the insulin, and in addition to these groups, there are combined therapies where medicines from Sos are administered to different groups mentioned above (2).

The most common standard treatment is the biguanides, which are characterized by the reduction of glucose produced by the liver and in turn benefits insulin resistance to regulate both the entry of glucose to the cells to be metabolized and the use of lipids by the tissues, without affecting the secretion of insulin by the pancreas. This mechanism prevents weight gain and hypoglycemia, in addition to improving the yipidic profile. The following side effects have been reported: diarrhea, nausea, vomiting, Flatulence, asthenia, indigestion, abdominal discomfort and headache (7). The contraindications of these medications are: chronic acidosis, kidney disease or dysfunction and congestive heart failure. Currently the most common treatment is Metformin. However, depending on the characteristics of the patient to be treated, the doses are modified, which can be distributed in several doses between meals. day to avoid gastrointestinal discomfort; currently there are long-acting tablets. This medication is not recommended in patients with renal insufficiency (8).

The exact mechanism by which this drug acts in the treatment of diabetes is not known, although its therapeutic benefits are widely known. Metformin does not affect the secretion of the pancreas, however, it is not active in the absence of insulin. It has been described as acting mainly by reducing gluconeogenesis and hepatic glycogenolysis, however it also reduces the absorption of glucose by the gastrointestinal tract while increasing the sensitivity to insulin by increasing glucose utilization by Peripheral tissues (7) by increasing the IP3 kinase activity of the insulin receptor (9) The average diabetic patient diagnosed with Diabetes Meilitus Type 2 has a rate of gluconeogenesis three times higher than normal, and apparently Metformin reduces this situation by more than one third (8). Metformin is not metabolized, but is excreted in the urine with an average elimination time of 6.2 hours (10).

The consumption of this drug in women suffering from ovulatory disorders, causes weight loss, as well as an improvement in both ovulation and fertility, decrease in the rate of abortions and gestational diabetes. In these patients, the administration of Metformin reduces the levels of sa hormone luteinizanie, as well as its acute release induced by agonists of the gonadotropin-releasing hormone (GnRH) (11), probably by decreasing the activity of cytochrome P450C ovarian and adrenai (12).

Metformin also improves the I profile of dyslipidemia, characteristic of most diabetic patients, reducing triglyceride values, as well as VLDL and LDL and, at times, has increased the HDL concentration (13),

To reduce the risks of microvascular complications in patients with Type 1 and Type 2 diabetes, such as retinopathy, nephropathy and neuropathy; As well as reducing the incidence of cardiovascular events, intensive therapies are used to administer insulin, to treat hyperglycemia and maintain stable glucose levels (14; 9). Sulfonylureas (SU), for example, help to promote the second phase of insulin secretion by pancreatic β cells, that is, the release of pre-formed insulin. Therefore, in order for SUs to exert their action, the presence of a critical mass of pancreatic beta cells with insulin-secreting capacity is required and there will therefore be a limitation in the use of this drug as a treatment in pancreatectomized patients (ie, with extirpation of the pancreas due to surgery) or with T1D. The SUs exert their action through high affinity receptors located in the pancreatic beta cells, the coupling of the SU to these receptors blocks the opening of the ATP-sensitive potassium channels, preventing the potassium from leaving the cell, propitiating the depolarization of the cell membrane. Calcium channels open up as a result of this reaction, increasing the intracellular calcium content and its binding to calmodulin, which, in short, would produce the microfilament contraction and the release of insulin. There are SU receptors and ATP-sensitive potassium channels in the heart and throughout the cardiovascular system that play a fundamental cardioprotective role against ischemia and the closure of them due to SUs could contribute to ischemia. However, this likely harmful effect seems notorious in Experimental studies where SU is administered at high doses acutely, does not seem to be relevant in clinical practice (15).

There are two groups of ED drugs, the first-generation drugs (íolbutamide, acetohexamide, toiazamide and ciorpropamide); and those of second generation (Glibenclamide, glimepiride, glípicida, giiquidona, gliclacida). The adverse effects of SUs are; hypoglycemia _> cardiovascular events, agranulocytosis, thrombocytopenia, bemolytic and aplastic anemia, rash, pruritus, headache, nausea, diarrhea, vomiting and hepatic porphyria. SUs are contraindicated in patients with hepatic or renal impairment. Among the most used, Glibenclamide is found, although currently as monotherapy is little used.

The bioavailability of Glibenclamide is approximately 70%, for the pharmaceutical form of tablets. It is rapidly absorbed after oral administration. Maximum serum concentrations are reached after 2 to 4 hours. The absorption of Glibenclamide is not significantly altered by food intake. The serum half-life of Glibenclamide is approximately 2 hours after intravenous administration, and 2 to 5 hours after oral administration; however, it has been suggested that in patients with DM, the half-life may be longer approximately 8 to 10 hours. There is no accumulation. Glyburide is mefaboh ^'za completely on E! Liver, The main metabolite is 4-trans-hydroxyigi-benclamide; another is the S-cis-bidroxiglibenciamide. The metabolites of Glibenclamide may have some hypoglycaemic effect (16). The excretion of the metabolites takes place in the urine and bile - approximately 50% per each way - and is complete after 45 a

72 hours In patients with renal insufficiency the excretion of metabolites by bile increases, which depends on the severity of renal failure. Glibenclamide crosses the placenta in minimal amounts. It is believed that Glibenclamide, like other sulfonylureas, is excreted in breast milk. Approximately in 30% of patients there is an insufficient response to any of the aforementioned treatments after 3 months of starting treatment; This is known as primary therapeutic failure. Subjects suffering from DM with hyperglycemia based! most of them present this failure, this is associated to the lack of compliance in the diet and / or the limited insulin reserve caused by a severe modification in the secretion of insulin by the pancreatic β cells.

In some cases, patients with DM undergoing oral pharmacological treatment for 6 months and with good metabolic control may stop responding to treatment, this is known as secondary therapeutic failure.

Studies indicate that between 5 and 10% of patients with DM have secondary therapeutic failure (17). This is evidenced by the progressive deterioration of insulin secretion from pancreatic β cells, which is part of the development of the disease .

It is important to know how to differentiate between true secondary failure and a transient loss of effectiveness of oral drugs due to an intercurrent disease since, in this case, you can regain good control with oral therapy after immediate and temporary treatment with insulin.

A therapeutic option in the face of primary or secondary failure is combined therapy (oral drugs or insulin), whose objective is to take advantage of the synergy or complementarity between the mechanisms of action of the drugs.

AND! Increased generation of reactive oxygen species (ROS) resulting from the metabolism of excess glucose and / or free fatty acid have been identified as contributing factors to the deterioration of the function of pancreatic β cells (18; 19). Because of ia Relatively low expression of antioxidant enzymes such as superoxide dismutase, catalase and glutathione peroxidases in the pancreas, pancreatic β cells may be highly vulnerable to damage when exposed to oxidative stress (20) as it plays an important role in cell deterioration β observed frequently in Type 2 Diabetes Meilitus,

Currently, antioxidants have been proposed for the protection of the pancreas against oxidative stress in Diabetes Meilitus (21). However, previously it had been shown that antioxidants have a reducing effect of oxidative stress improving the state of the kidney and pancreas in models of rats with Diabetes Meilitus, being that the protection of the pancreas against oxidative stress can contribute positively to a hypoglycemic effect ( 22; 23),

In US Pat. No. 8,506,997, by Soto-Peredo, the invention and manufacture of a pharmaceutical compound constituted by silymarin (extract of flavonoid origin) and carbopol (hydrophilic polymer) whose purpose is to serve in the regeneration of pancreatic tissue, as well as as of endogenous secretion cells that are damaged during Diabetes Meilitus by the administration of insulin and diabetogenic agents, such as Alloxan (24; 25).

The treatment of Metformin in conjunction with Gilbenclamide is indicated for non-insulin dependent diabetes (Diabetes Meilitus Type 2), not ketoacidosis, is used when dietary measures and mono-therapy with suifonylureas in patients are not sufficient to achieve a good control of the levels glycemic As well as patients who are under dietary regimen and with failure to mono-therapy with hypoglycemic agents.

In addition, within the combined treatment of sulfonylurea plus biguanide, a greater stimulus is needed for the production of insulin by pancreatic cells, which is achieved by increasing the dose of sulfonylurea. At present, a beneficial effect has been demonstrated by adding an antioxidant as a complement to Glibenclamide or Metformin, improving the control of glycaemia in diabetic rats (26). In several studies, a significant reduction in fructosamine levels has been observed when treatment with Glibenclamide or Metformin combined with an antioxidant has been used. Therefore, this suggests that these hypoglycemic drugs in combination with antioxidants produce better glycemic control (22; 23).

It is not yet clear how some antioxidants contribute to the decreased concentration of fructosamine. Previous studies have concluded that antioxidants such as vitamins C and E reduce HbA1c levels by inhibiting protein glycation (27). Likewise, it was observed that in the groups of diabetic animals where a decrease in fructosamine levels was shown, the blood glucose concentration was also significantly reduced. Therefore, based on these results, it can be suggested that the combination of hypoglycemic drugs with some antioxidant can reduce the formation and / or the detrimental effects of advanced glycation end products (AGEs), which may delay the development and the progression of complications caused by diabetes (29).

Today, phytotherapy has become relevant because of the large number of antioxidant extracts that have shown benefits for humans. For example, the extract of Süybum marianum, silymarin and derivatives have become important in the treatment of Diabetes Melitis. Recent studies have shown that the use of silybin in the treatment of diabetes induced by streptozocin in Sprague Dawley rats (13), significantly decreases the concentration of glucose, as well as the profile of lipids present in the blood. Likewise, it prevents oxidative stress caused by the antibiotic, since it has been shown to restore normal levels of anioxidizing molecules that are affected by the disease and the high presence of reactive oxygen species. However, the effects of silybin in conjunction with hypoglycemic drugs, such as Metformin and Glibenclamide for the treatment of Diabetes, remain unknown.

OBJECTIVES OF THE INVENTION

AND! The main objective of the present invention is to achieve a synergistic effect between two hypoglycemiants and an antioxidant.

As secondary objectives:

Reduce the dose of the combination of hypoglycemic agents, reducing the doses of the antioxidant in the composition of the drug.

Delay the development and progression of complications caused by diabetes.

Achieve the right moment of assimilation and availability of the antioxidant and the combination of hypoglycemic agents,

And all those objectives and advantages that will become apparent with the reading of the present description together with the examples that illustrate the present invention.

BRIEF DESCRIPTION OF THE INVENTION

Silybin, one of the most active components of the whole that makes up the symimarm, has shown beneficial effects for the patient. human being in the treatment of chronic-degenerative diseases (30). However, being a flavonoid extract, it is characterized by its low absorption and bioavailability in the organism. Currently there is a phytosomai complex of silybin with phosphatidylcholine (Siiipbos®), the latter allows the antioxidant to be soluble and permeable to the cellular lipid membrane. The complex silibina more fosfatidilcolina {Siiiphos®) has a fast absorption and greater bioavailability in comparison with the extracts of silymarin and silymarin studied individually. The Cmax is 298 ng / mL and the Tmax is 1.4-1.6 hours, after dose administration equivalent to 360 mg of silybin (6),

With regard to hypoglycemic agents present in the invention, Metformin and Giibenclamide, it was found that the former presents an alkaline pKa value and therefore it would be incompatible with silybin since it does not interact positively with oxidizing agents or strong bases. According to the above, it is suggested that Metformin go through a granulation stage prior to the manufacture of the drug. Likewise, it is suggested to modify the release of Metformin for about 4 hours more after the half-life time of silybin which is less than 4 hours.

For its part, the Giibenclamide has not been found to present incompatibility with the antioxidant, however, it is suggested a sustained release of! This drug, due to the short life time of silybin.

It is not recommended that the siibin plus phosphotidylcholine complex (Siiiphos ©) be the active principle of prolonged release, because the hybrid bonds of silybin with the phosphatidylcholine molecules could affect the bioavailability of the product and that silibin has a T _max x in plasma for 2 hours, whereas Metformin has a Tma * of 3 hours and this is affected by food intake. Therefore, it is concluded that for manufacturing, the triconjugate formed for the complex of silybin plus phosphatidylcholine (Siiiphos®) plus Glibenclamide and Metformin, the latter should be lightly granulated to offset the absorption after 3 hours and is not a competitive substrate for the silibine and phosphatidylcholine complex (Siliphos®),

PHARMACEUTICAL FORM OF THE MEDICINAL PRODUCT

Tablets: This pharmaceutical form is chosen for its easy administration and dosage, as well as easily manipulating the absorption and dissolution requirements of active ingredients with well-known technologies.

FORMULATION OF THE EDUCATION AND FUNCTION OF THE EXCIPIENTS

The formulation is:

> Silybin Complex + Phosphatidylcholine (Silíphos®) -Principio Activo,

> Metformin Hydrochloride-Active Principle.

> Giibenclamide-Active Principle.

> Polyvinylpyrididinone K 90/32-Binder.

> Microcrystalline cellulose type 102-Excipient of compression,

> Sodium lauryl sulfate-Anionic surfactant.

> Croscarmellose sodium-disintegrant,

> Magnesium Stearate-Lubricant,

> Colloidal silicon dioxide-Lubricant.

> Ethanol-Solvent.

> Aquarius Prime BT419769 Purple-Aesthetic coating of the tablet. > Purified water-Solvent for coating.

Because it was observed that the complex Sílibina más fosfatidilcolína (Siliphos®) is a fibrous raw material, it was difficult the disintegration of the tablet in the dissolution tests so it was opíó by the addition of surfactant agent {Laurii sodium sulfate) and so the tablet managed to disintegrate, in less than 15 minutes.

The formula achieves the dissolution of the three active principles in less than one hour.

The dissolution of Metformin and Glibenclamide is the closest to the desired for the product to be developed, so the assessments for this formula were made.

For the final formula, differential scanning calorimetry studies were carried out, in order to show if there is incompatibility between the active principles with some of the excipients used in the formula, being able to observe that there is no type of degradation or incompatibility between the combinations evaluated.

With the previous granulation of Metformin, longer release times were obtained, which resulted in a longer time in the absorption of metformin, increasing the unique absorption of the Silibin plus phosphatidylcholine complex (Siliphos®). Likewise, the absorption of metformin is affected by food intake for up to 6 hours, while for the complex of silybin plus phosphaididylcholine (Siliphos®) and Glibenclamide, food does not interfere with its absorption.

By way of conclusion, the final formula is suitable for the three active ingredients, the complex of Silybin + Phosphatidylcholine (Siliphos®), Metformin and Glibenclamide), since it maintains chemical stability in short periods involving the manufacture and immediate analysis of! product (tablet). The amounts in mg per tablet are described below

DETAILED DESCRIPTION OF THE INVENTION üetforrrsina

The maximum recommended daily dose of Metformin is 2,550 mg in adults and 2,000 mg in young patients over 18 years of age. Metformin should be administered in divided doses with meals. Using up to 5 Metformin tablets of 500 mg or up to 3 Metformin tablets of 850 mg.

Süibirsa + Fosfaiid ilcolina complex (Siliphos®)

The siiibin + phosphatidylcholine complex is marketed under the brand name Siliphos® and doses of siiibine greater than 360 mg three times daily for three weeks without toxic effects have been administered in humans. In preclinical studies the lethal dose 50 (LD50) reported (tolerance level) in dogs was 300 mg / kg, mice of 1,000 mg / kg, rabbits of 300 mg / kg and rats of 900 mg / kg.

The duration of treatment depends on the underlying condition in which it has been indicated. It may be administered indefinitely, since it has no cumulative or toxic effect.

Güibanclamide

In patients with a tendency to hypoglycemia or weighing less than 50 kg, the administration of 2.5 mg before breakfast or the main meal is recommended. If the blood glucose results are satisfactory, the same dose should be maintained. In case the dose needs to be increased, it will be increased from 2.5 mg in 2.5 mg in intervals of one to two weeks with constant monitoring of blood glucose, the maximum increase of single daily dose should not be greater than 10 mg. In patients who use fractionated doses, in cases requiring more than 10 mg / dsa, the increase should be divided before lunch or dinner at a rate of 2.5 mg each time, with strict monitoring. The maximum daily dose is 15 to 20 mg, ietformiria / Glibencyamide / SHibin Complex + Phosphatidylcocine

{Siliphos®}

The dose of this combination (considering Mephorphine between 230 and 250 mg, Glibenclamide between 15 and 20 mg, and the complex SHibina + FosfatidilcoMna between 180 and 220mg) will be of 1 tablet a! day during the main meal, without spending 2 g of metformin a day, then this daily dose may be decreased at the discretion of the doctor. This combination offers all three drugs in a single pharmaceutical form. The initial dose of this combination will be 1 tablet per day and adjusted according to the patient's metabolic control at the discretion of the attending physician, without exceeding 4 tablets per day.

One of the embodiments of the present invention is a tablet with the following composition;

The manufacturing process of this tablet consists of the following series of steps; a) Metformin is sieved with a number 12 mesh and fed to the high-cut mixer with Polyvinylpyrrolidone PVP K29 / 32 where they are mixed for 3 minutes at 114 rpm, b) The result is slowly fed to a mixer-granulator and added the ethanol by rotating the mixer at 114 rpm and a crusher speed of 1800 rpm. c) The product thus obtained is transferred to the tray dryer, reaching a temperature of 50-80 ° C _; for 3 hours, removing the trays every hour to favor e! dried with a relative humidity of 1.5%. In this step, the ethanol evaporates. d) The product at said temperature and humidity is passed to grind and sieve in a conical mesh mill with a diameter of 1 mm, residual moisture by thermobalance <1.5%. e) It is discharged into a bin mixer with the addition of Type 102 microcrystalline cellulose, sodium croscamellose, sodium lauryl sulfate, colloidal silicon dioxide and the Silybin + Phosphatidncoiin complex (Sillphos®) where it is mixed at a rate of 10 rpm for 15 min. Magnesium stearate is added here and mixing continues at the same speed for 3 minutes. f) The mixture is tabletted making a tablet with average weight of 750 ± 3% mg, individual weight of 750 ± 5%, with a hardness of 9 to 11 kP, friability lower than 1% and disintegration no greater than 15 minutes. g) The tablet is coated with a coating polymer, such as Aquarius Prime BT419769 Purple dissolved in water, obtaining a tablet with an average weight of 850 ± 3% mg, individual weight of 850 ± 5%.

EXAMPLES

Example 1. Clinical study to evaluate the safety between the drug in Research GHbersclamlda / ietformina / Silibina plus Phosphatidylcholine fSiiiphos®} and the reference medicine Giibeoclamida / ietforrrsir¡a.

A study was conducted to evaluate the safety of the dosage between e! Research drug Glibenlenide / Metformin / Silybin plus Phosphatidylcholine (Siiiphos®) and the reference medicine Glibenclamide / Metformin. The study presented a single dose design, two treatments and a washout period of 07 days between the study treatments. Twenty-eight healthy subjects of both genders were recruited, a diet of approximately 2,800 calories was administered, the doses used were: Glibenlenide 5 mg / Metformin 250 mg / Silibine plus Phosphatidylcholine (Siiiphos®) 200 mg and Glibenlenide 5 mg / Metformin 250 mg, and different safety variables were obtained along the length of! study through the quantification of vital signs.

Oral administration of the formulations did not produce significant clinical changes in vital signs [systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate and temperature) and were reported as adverse events, one subject with tachycardia, one with fever and another with low-grade fever, the rest was within the normal range. The subjects did not present any allergic reaction to the medication.

The results suggest that the formulations studied in the form of tablets of: Glibenlenide 5 mg / Metformin 250 mg / Silybin plus Phosphatidylcholine (Siiiphos®) 200 mg and Glibenlenide 5 mg / Metformin 250 mg, produce similar effects on the vital signs evaluated, Ai no there are significant clinical differences and no suspicion of serious adverse reactions during the study; It was concluded that from the clinical point of view the studied formulations produce similar effects and are safe for their use. Example 2. Clinical study to evaluate the drug interaction between the investigational drug Glibenclamide / ithformine / S IIibin plus Phosphatidylcholine (Siliphos®) and the reference medicine Glibenclamide /

A study was carried out to evaluate the drug interaction by comparing the pharmaco-clinical characteristics of the dosage between the investigational drug Glibenclamide / Metformin / Silybin plus Phosphatidylcholine (Siiiphos®) and the reference medicine Glibenclamide / Metformin.

The same protocol was applied as in the previous example. The concentration of IVIetformin and Glibenclamide in plasma was quantified using high performance liquid chromatography collected by mass spectrometry.

It was found that the combination of Silybin plus Phosphatidylcholine {Siiiphos®) stabilizes the effect of the therapeutic action of Metformin by keeping the concentration of said drug constant for a longer time (Table 1),

Table 1. Metformin behavior in the different formulations

For the behavior of Glibenclamide no differences were found between the formulation with and without Silibine plus Phosphatidylcholine (Siiiphos®) (Table 2)

Table 2. Glibenzyamide behavior in the different formulations

Example 3. Clinical Trial Fa BB III, sobr ^€> Oo evaluad efficiency and use segorida d silybin more Fosfat idilcolina

(Siiiphos®) 200 mg with the aid of hypoglycaemic agents for corsets. of Diabetes Mellitus Type 2.

During this study, the efficacy and safety of Silybin plus Phosphatidylcholine (Siiiphos®) was evaluated as an adjunct to the hypoglycemic agents Metformin and Glibenzamide in the treatment of DM2.

The trial presents a phase III, double blind, controlled, multicenter, clinical study design with two study groups (investigational drug Glibencide / Metformin / Silybin plus Phosphatidylcholine (Siiiphos®) and reference drug Glibenzyamide / Metformin ). The treatments are administered for a period of 180 days and a sample is taken to evaluate the levels of glycosylated hemoglobin at 30, 60, 90, 120, 150 and 180 days of treatment, as well as the blood glucose levels.

A total of 299 patients were recruited, with a diagnosis of 2 to 5 years of type 2 diabetes mellitus, ages 40 to 85 years, of both genders. Of these subjects, preliminary results are available up to the third month of treatment. It has been observed for both groups (TxA: Gübenciamide / Metformin and TxB, Gibenzide / Metformin / Silibin plus Phosphatidylcholine (Siliphos®)), a decrease in the Blood Glucose concentration and in the levels of Glycosylated Hemoglobin as patients have advanced in the months of treatment (Fig. 1 and Fig. 2). It is worth mentioning that in order to observe the adjuvant effect of Silybin plus Phosphatidyloicin (Siliphos®), treatment times of more than three months are required, because we must wait until the end of the study to be able to conclude about the triconjugate formulation,

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Claims

1. Pharmaceutical composition for the control of blood glucose concentration in newly diagnosed patients, characterized by comprising a combination of Meiformine, Glibenclamide complex of Silybin + Fosyatidylcholine (Siliphos ®)

2, Pharmaceutical composition for the control of blood glucose concentration, as claimed in the preceding claim, further characterized in that the Metforrnin / Glibenclamide / Silybin + Phosthynaidylcholine (Siliphos ®) complex ratio is from 1 to 1.25,

3, Pharmaceutical composition for the control of blood glucose concentration, as claimed in the preceding claim, also characterized in that metforrnin is in the tablet in the form of particles coated with Polyvinylpyrrolidone PVP K29 / 32.

4, Pharmaceutical composition for controlling blood glucose concentration, as claimed in the preceding claim, also characterized in that the medical form consists of a tablet, comprising crystalline cellulose Type 102, sodium Croscarmellose, Laurii Sodium Sulfate , Colloidal Silicon Dioxide, Magnesium Stearate and a coating of the Aquarius Prime tablet BT419769 Purple,

5. Pharmaceutical formulation for the control of blood glucose concentration, as claimed in the previous claim, characterized by comprising:

Metformin Hydrochloride 250.0000 Active Ingredient GNbencI Amide 5.0000 Active Principle Polyvinyl Pyrrolidone (PVP)

45.0000 Binder

K29 / 32

Excipient of

Crystalline cellulose Type 102 195.9000

compression

Croscarmellose sodium 12.8000 Disintegrant

Suryactant

Sodium lauryl sulfate 37.5000

anonic

Colloidal silicon dioxide 1.9000 Lubricant

Magnesium Stearate 1.9000 Lubricant

Eilanol ** 17.5900 Solvent

** It evaporates during drying.

*** It evaporates during the coating.

8, Method for the manufacture of a pharmaceutical composition for the control of blood glucose concentration, characterized by comprising the following series of steps, a) Metformin is screened with a number 12 mesh and fed to the high cut blender with Polyvinylpyrrolidone PVP K29 / 32 where they are mixed for 3 minutes at 114 rpm. b) The result is fed slowly to a mixer-granulator and the ethanol is added by rotating the mixer at 114 rpm and a crusher speed of 1800 rpm. c) The product thus obtained is transferred to the tray dryer, reaching a temperature of 50-60 ° C, for 3 hours, removing the citiaroies every hour to favor drying with a relative humidity not higher than 1.5%. In this step, the ethanol evaporates, d) E! product at this temperature and this humidity is passed to grind and sieve in a mill of conical meshes with a diameter of 1 nm, with a residual humidity by thermobalance ≤ 15%. e) It is discharged in a bin mixer adding glibenclamide, PH102 microcrystalline cellulose, sodium croscamellose, sodium lauryl sulfate, colloidal silicon dioxide and the Silibin + Phosphatidylcholine complex (Siliphos®) where it is mixed at a rate of 10 rpm for 15 min. After the previous step, the magnesium stearate (previously sieved by a No. 30 mesh) is added and it is continued mixing at the same speed for 3 minutes, f) The residual humidity is measured with a thermobalance, verifying that it is not greater than 1.5% g) The mixture is tabletted with a tablet with an average weight of 750 ± 3% rng, an individual weight of 750 mg ± 5%, with a hardness of 9 to 11 kP, a friability of less than 1%, and a disintegration no more than 15 min. h) The tablet is coated in a drum with a coating polymer, using the Aquarius Prime BT419769 Purple dissolved in purified water, resulting in a tablet with an average weight of 850 ± 3% mg, 850 mg ± 5% individual weight.

7. Method for the manufacture of a pharmaceutical composition for e! control of blood glucose concentration, as claimed in the preceding claim, further characterized in that the mixing in step a) is carried out for 3 minutes at 114 rpm and because step c) comprises adding ethanol, by rotating the granulator at 114 rpm and a crusher speed of 1800 rpm.